British Association of Urological Surgeons Consensus statements on the management of ketamine uropathy.

OBJECTIVES: To provide guidance in the form of consensus statement in the management of ketamine uropathy. METHODS: A literature review of ketamine uropathy was performed. The consensus method was of a modified nominal group technique and has been use in the previous British Association of Urological Surgeons (BAUS) consensus documents and was led by the Female, Neurological and Urodynamic Urology Section of the BAUS. RESULTS: A number of consensus statements detailing the assessment and management of urological complications relate to the recreational use of ketamine (ketamine uropathy) in both elective and emergency urology settings. CONCLUSION: Comprehensive management pathway for ketamine-related urinary tract dysfunction and uropathy has been detailed.

Relationship between sexual and bladder dysfunction in women consuming ketamine.

BACKGROUND: Although ketamine has become the second most popular recreational drug in Taiwan, there have been very few reported studies that investigated female sexual dysfunction (FSD) in ketamine abusers (KAs). AIMS: We sought to compare the difference between street and hospital KAs and explored the risk factors for FSD and lower urinary tract symptoms (LUTS) in KAs. METHODS: In this cross-sectional study, female KAs aged 18 years or older were invited to complete anonymous questionnaires during an educational course provided by the departments of substance control and prevention of the local government or under the instruction of medical providers at a urology clinic. Data were reported as median (IQR) and OR and analyzed with commercial statistical software. OUTCOMES: Key outcome measurements were illicit drug use history, FSD symptoms, and LUTS severity. RESULTS: We included 139 women (104 street and 35 hospital KAs) with a median age of 27.08 years. FSD was reported in 76% of all the participants (street vs hospital KAs, 68% vs 97%, P < 0.001). LUTS (Interstitial Cystitis Symptom Index [ICSI] + Interstitial Cystitis Problem Index [ICPI] ≥12) was found to be a significant risk factor for FSD in KAs. More hospital KAs (71%) reported experiencing LUTS (ICSI + ICPI ≥12) than street KAs (8%, P < 0.001). Longer duration of ketamine use (≥36 months) and mild to severe psychological symptoms (5-item Brief Symptom Rating Scale [BSRS-5] ≥6) were significant risk factors for LUTS. CLINICAL IMPLICATIONS: Sexual problems among KAs should not be overlooked since more severe sexual dysfunction was observed in patients reporting LUTS. STRENGTHS AND LIMITATIONS: To our knowledge, the present study is the largest study using validated and reliable questionnaires to examine FSD in KAs and also the first study to include street KAs. The main limitation of this study is using self-report questionnaires as they are subjective and susceptible to human errors and recall biases. CONCLUSIONS: Women who abused ketamine and reported experiencing LUTS were found to be more likely to have FSD.

Molecular pathways underlying tissue injuries in the bladder with ketamine cystitis.

Ketamine cystitis (KC) is a chronic bladder inflammation leading to urinary urgency, frequency, and pain. The pathogenesis of KC is complicated and involves multiple tissue injuries in the bladder. Recent studies indicated that urothelium disruption, lamina propria fibrosis and inflammation, microvascular injury, neuropathological alterations, and bladder smooth muscle (BSM) abnormalities all contribute to the pathogenesis of KC. Ketamine has been shown to induce these tissue injuries by regulating different signaling pathways. Ketamine can stimulate antiproliferative factor, adenosine triphosphate, and oxidative stress to disrupt urothelium. Lamina propria fibrosis and inflammation are associated with the activation of cyclooxygenase-2, nitric oxide synthase, immunoglobulin E, and transforming growth factor ß1. Ketamine contributes to microvascular injury via the N-methyl-D aspartic receptor (NMDAR), and multiple inflammatory and angiogenic factors such as tumor necrosis factor α and vascular endothelial growth factor. For BSM abnormalities, ketamine can depress the protein kinase B, extracellular signal-regulated kinase, Cav1.2, and muscarinic receptor signaling. Elevated purinergic signaling also plays a role in BSM abnormalities. In addition, ketamine affects neuropathological alterations in the bladder by regulating NMDAR- and brain-derived neurotrophic factor-dependent signaling. Inflammatory cells also contribute to neuropathological changes via the secretion of chemical mediators. Clarifying the role and function of these signaling underlying tissue injuries in the bladder with KC can contribute to a better understanding of the pathophysiology of this disease and to the design of effective treatments for KC.

Specific Impacts of Ketamine on Bladder Dysfunction and Associated Histological Alterations in Rats-A Time Course Validation through Transmission Electron Microscopy.

This study explored the specific effects of ketamine on bladder function followed by a sequence of histological changes in a rat bladder at fixed time course intervals. The rats were grouped into normal control and experimental animals, and ketamine (100 mg/kg/day) was administrated to the experimental animals for 2, 4, and 8 weeks, respectively; similarly, the control animals received saline. All animals were evaluated for bladder function and histological responses to the treatment. Ultrastructural changes were observed by transmission electron microscopy (TEM). The results showed progressive bladder dysfunctions with hyperactive bladder conditions according to the time course and frequency of exposure to ketamine. Significantly, decreased inter contraction intervals, residual urine volume, peak micturition pressure, and increased micturition frequency were observed. Bladder histology results revealed substantial inflammation and comprehensive submucosa edema in week 2 and 4 rats along with fibrosis and significant bladder detrusor hypertrophy in week 8 rats. TEM analysis revealed bladder wall thickening, deformed blood vessels, detrusor hypertrophy, wobbled gap junction, and barrier dysfunction at different time course levels in experimental animals. These results provided a profound knowledge about the prognosis and step-by-step pathophysiology of the disease, which might help in developing new therapeutic interventions.

The effects of recreational ketamine cystitis on urinary tract reconstruction - a surgical challenge.

OBJECTIVES: To identify the rate of postoperative complications in patients who require surgical reconstruction for ketamine-induced urinary tract dysfunction and to identify any predictors for poor postoperative outcome with subsequent management strategies. PATIENTS AND METHODS: A retrospective review of data collected between 2007 and 2017 of all patients with ketamine-induced urinary tract disease was performed. Evaluation included computed tomography urogram, cystoscopy, and biopsy. Indications and outcomes for surgical intervention were assessed. RESULTS: In all, 44 patients were identified of which 68% were male. The mean (range) age at presentation was 31 (23-55) years. All bladder biopsies confirmed an eosinophilic inflammatory infiltrate. A significant proportion of patients (81.8%) were found to have reduced cystoscopic bladder capacity of <300 mL (mean 196, range 25-550 mL). In all, 29 patients were treated conservatively with a view to symptom resolution. Two patients underwent dilatation for urethral strictures. Four patients underwent repeated intra-detrusor onabotulinum toxin injection with minimal subjective symptom relief. Two of these patients proceeded to have major reconstruction. Indications for urinary tract reconstruction included intractable symptoms, high-pressure compliance loss with renal compromise and ureteric obstruction. Patients were advised to abstain from ketamine use for a minimum of 6 months prior to consideration of surgical intervention. A total of 14 patients underwent major reconstruction. Surgical intervention included ileal conduit urinary diversion, augmentation cystoplasty with or without Mitrofanoff channels, ureteric re-implantation, and cystectomy with neobladders. Complications included anastomotic leaks, ureteric strictures, adhesional small bowel obstruction, renal failure, and sepsis. Overall, complications occurred in 10/14 patients. CONCLUSION: In a tertiary high-volume reconstructive unit, ketamine patients were at high risk of significant perioperative complications. There did not appear to be any other common factor apart from their use of ketamine, and the significant inflammatory change associated with this. We recommend meticulous preoperative evaluation and multidisciplinary consultation for all patients to determine optimal treatment strategies.

Intact urothelial barrier function in a mouse model of ketamine-induced voiding dysfunction.

Ketamine is a popular choice for young drug abusers. Ketamine abuse causes lower urinary tract symptoms, with the underlying pathophysiology poorly understood. Disruption of urothelial barrier function has been hypothesized to be a major mechanism for ketamine cystitis, yet the direct evidence of impaired urothelial barrier function is still lacking. To address this question, 8-wk-old female C57BL/6J mice were injected intraperitoneally with 30 mg·kg(-1)·day(-1) ketamine for 12 wk to induce ketamine cystitis. A spontaneous voiding spot assay showed that ketamine-treated mice had increased primary voiding spot numbers and smaller primary voiding spot sizes than control mice (P < 0.05), indicating a contracted bladder and bladder overactivity. Consistently, significantly increased voiding frequency was observed in ketamine-treated mice on cystometrograms. These functional experiments indicate that ketamine induces voiding dysfunction in mice. Surprisingly, urothelial permeability in ketamine-treated mice was not changed when measured using an Ussing chamber system with isotopic urea and water. Mouse urothelial structure was also not altered, and intact umbrella cell structure was observed by both transmission and scanning electron microscopy. Furthermore, immunostaining and confocal microscopy confirmed the presence of a well-defined distribution of zonula occuldens-1 in tight junctions and uroplakin in umbrella cells. In conclusion, these data indicate that ketamine injection induces voiding dysfunction in mice but does not necessarily disrupt mouse bladder barrier function. Disruption of urothelial barrier function may not be the major mechanism in ketamine cystitis.

Management of ketamine cystitis: National Guidelines from the French Association of Urology (CUROPF/CTMH).

OBJECTIVE: The objective of the CUROPF and CTMH was to establish recommendations about ketamine induced uropathy management. METHODS: A systematic review of the literature was conducted on Pubmed/Medline by the members of the French committees of female urology and male lower urinary tract symptoms focusing on the epidemiology, pathophysiology, diagnosis and treatment of ketamine induced uropathy, evaluating references and level of evidence. RESULTS: Recommendations include epidemiology, pathophysiology, diagnosis and treatment of ketamine induced uropathy. It represents a rising healthcare issue, with major augmentation of ketamine consumers and new patients across the world. Several pathophysiology pathways are suspected and need clinical validation. The diagnosis is clinical, with hyperactive bladder symptoms mostly including pollakiuria, but also lower urinary tract symptoms, and histological, requiring bladder biopsies to rule out carcinoma and show specific features and inflammation. Therapeutics are currently limited and non-specific, combining abstinence, hydrodistension, pentosane polysulfate and Botox injections. Complex reconstructive surgeries should be avoided and be considered as a last resort. CONCLUSION: These guidelines should provide tools to help every physician confronted to ketamine induced uropathy patients, which represents a growing issue. Hopefully, this work will allow the improvement of the screening, management and care of ketamine induced uropathy in the future.

Ketamine-induced uropathy: A narrative systemic review of surgical outcomes of reconstructive surgery.

Aims: Refractory ketamine-induced uropathy (KU) (RKU) has devastating effects on the lower urinary tract leading to ureteral obstruction and even renal failure. The only effective treatment for RKU is major surgical reconstruction or urinary diversion. Nevertheless, there is a paucity of awareness about this destructive condition; the aim of this study is to conduct a narrative systemic review of all surgical outcomes of RKU. Methods: This is an English language literature review of surgical outcomes in KU patients who underwent reconstructive lower urinary tract surgery or urinary diversion through 5 August 2022. Two independent researchers assessed the relevance of each paper and disputes were settled by a third party. In-vitro, animal studies, letters to the editor and papers that did not evaluate surgical outcomes were excluded. Results: Of the 50 763 identified articles, 622 were relevant based on title, 150 based on abstract, but only 23 papers were relevant by content. In all, 875 patients were documented as having KU, of whom 193 (22%) underwent reconstructive surgery. The data were disconcerting, as the apparent rapid progression from the beginning of KU to end-stage bladder was only a 1-year difference of ketamine abuse between those patients who required surgery (4.4 years) and those that did not (3.4 years). Conclusions: The data suggest that the time interval from the beginning of ketamine-induced uropathy to the end-stage bladder may be measured in months, confounding decision making. There is a dearth of literature about KU, and more research is needed to better understand this pathology.

Intravesical Instillation of Norketamine, a Ketamine Metabolite, and Induced Bladder Functional Changes in Rats.

This study aimed to determine the mechanism of ketamine-induced cystitis without metabolism. A total of 24 adult male Sprague-Dawley rats were separated into control, ketamine, and norketamine groups. To induce cystitis, rats in the ketamine and norketamine groups were treated with intravesical instillation of ketamine and norketamine by mini-osmotic pump, which was placed in subcutaneous space, daily for 24 h for 4 weeks. After 4 weeks, all rats were subjected to bladder functional tests. The bladders were collected for histological and pathological evaluation. Compared to control, ketamine treatment demonstrated an increase in the bladder weight, high bladder/body coefficient, contractive pressure, voiding volume, collagen deposition, reduced smooth muscle content, damaged glycosaminoglycan layer, and low bladder compliance. Compared to ketamine, norketamine treatment showed more severe collagen deposition, smooth muscle loss, damaged glycosaminoglycan layer, and increased residual urine. Intravesical administration of ketamine and norketamine induced cystitis with different urodynamic characteristics. Norketamine treatment caused more severe bladder dysfunction than ketamine treatment. Direct treatment of the bladder with norketamine induced symptoms more consistent with those of bladder outlet obstruction than ketamine cystitis. Detailed studies of cellular mechanisms are required to determine the pathogenesis of ketamine cystitis.

Risk Factors of Lower Urinary Tract Syndrome among Ketamine Users.

OBJECTIVE: This study investigated the risk factors of ketamine associated-lower urinary tract symptoms (LUTS), such as duration of use, dosage of ketamine, co-occurring substance use of other psychoactive drugs, comorbidities, and depression. METHODS: This study was a cross-sectional survey. LUTS was assessed with the O'Leary symptom and problem index (OSPI) scores. We included the comorbidities of interstitial cystitis/painful bladder syndrome (IC/PBS) as comorbid factors. Depression was evaluated based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM 5). Duration of use, dosage of ketamine and the OSPI scores were subjected to log transformation because of the skewed distribution. RESULT: Among 143 participating ketamine users, 25 (17.5%) had LUTS. Duration of ketamine use was significantly positively correlated with OSPI scores (adjusted ß [95% CI], 0.21 [0.06-0.35] in log-log model), which equaled a 10% increase in months of ketamine-use increased OSPI scores by 2.02 %. Female and depression were significantly associated OSPI scores (adjusted ß [95% CI], 0.20 [0.03-0.37], 0.49 [0.29-0.70], respectively in the log-linear model), with OSPI scores being 1.22 times higher in female, and 1.63 times higher in ketamine users with depression. Dosage of use was not significantly associated with OSPI scores (adjusted ß [95% CI], 0.04 [-0.12 to 0.20], P = 0.64 in log-log model), likewise with comorbid diseases (adjusted ß [95% CI], 0.07 [-0.08 to 0.21], P = 0.36 in log-linear model). CONCLUSION: Depression and longer duration of exposure to ketamine are significantly associated with the development of LUTS among ketamine users. Early evaluation and intervention of depression should be considered in patients of ketamine-associated LUTS.